Comorbidity of Alcoholism and Anxiety Disorders: The Role of Family Studies.

People with alcoholism frequently also suffer from an anxiety disorder. The mechanisms underlying this comorbidity remain unclear. Clinical findings indicate that anxiety disorders may lead to the development of alcoholism. Conversely, alcoholism may contribute to the development of anxiety symptoms. Family studies have reported elevated rates of anxiety disorders in the relatives of patients with alcoholism and vice versa, suggesting that both disorders may share some susceptibility factors. The Yale Family Study of the comorbidity of alcoholism and anxiety confirmed these observations. The study also found gender-specific differences in the risk for some comorbid anxiety disorders. Moreover, the relatives of people with alcohol dependence or anxiety were at increased risk for alcohol dependence but not alcohol abuse.

N umerous clinical and epidemi Riggs 1995; Schuckit and Hesselbrock people with phobic states rather than ological studies 1 have dem 1994).The confirmation of an associa panic or generalized anxiety states onstrated the comorbidity of tion between alcoholism and anxiety (for a definition of these terms, see alcoholism 2 and anxiety disorders (re disorders in largescale epidemiologi the following section).viewed in Wesner 1990; Kushner et al. cal studies suggests that the observed This article provides an overview 1990; George et al. 1990; Crowley and frequent comorbidity is not attributable of the prevalence and the potential to the fact that patients with both disor mechanisms underlying the comor 1 Clinical studies use relatively small numbers ders may be more likely to enter treat bidity of alcoholism and anxiety dis of patients with the disorder under investiga ment and thus be overrepresented in orders.The article also describes how tion as their subjects (e.g., alcoholics or people clinical studies (Regier et al. 1990a; family studies may help elucidate the with an anxiety disorder who are undergoing association between these disorders treatment).Therefore, all subjects of a clinical Kessler et al. 1996).The mechanisms and presents data from a recent family study share certain characteristics.Epidemiologi underlying this comorbidity remain un cal studies, in contrast, include large numbers known, largely because of the highly study conducted at Yale University.
of subjects who are drawn from the general variable manifestations (i.e., the het population.Thus, they include people with and without the disorder under investigation who erogeneity) of both disorders and the

ANXIETY DISORDERS
have not been selected on the basis of specific disparate methodologies employed in clinical characteristics.
the various studies.In general, however, The anxiety disorders of adulthood 2 The term "alcoholism" as used in this article the comorbidity of alcoholism and compose one of the most common encompasses the diagnoses of both alcohol anxiety appears to be far more common groups of psychiatric disorders in the abuse and alcohol dependence as defined in in women than in men, in individuals general population, with prevalence the American Psychiatric Association's Diag nostic and Statistical Manual of Mental Dis diagnosed with alcohol dependence rates in the community as high as 25 orders, Fourth Edition.
rather than alcohol abuse, and among percent (Kessler et al. 1994).Anxiety is medically defined as "the apprehen sion of danger and dread accompanied by restlessness, tension, tachycardia 3 and dyspnea 4 unattached to a clearly identified stimulus" (Stedman 1996, p.187).Several different subtypes of anxiety exist that are defined by dif ferences in the specific stimulus (or lack thereof) and the nature of the anxiety.The American Psychiatric As sociation's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) specifies 12 major categories of anxiety disorders, such as panic disorder with or without agoraphobia, specific or social pho bia, generalized anxiety disorder, or substanceinduced anxiety disorder.Some of the more common anxiety disorders and their symptoms include the following: • Panic disorders with or without agoraphobia are characterized by panic attacks-sudden episodes of intense fearfulness or terror that are accompanied by autonomic nervous system reactions, such as palpita tions (i.e., a pounding or racing of the heart), sweating, or shortness of breath.
• Agoraphobia with and without ac companying panic disorder involves the avoidance of places or situa tions from which escape might be difficult-for example, being in a crowd of people, or traveling on a bridge or in an elevator.
• Phobias are characterized by specific fears of objects or situations, such as spiders and heights (i.e., specific phobia) or speaking in public (i.e., social phobia).

Prevalence of CoOccurring Alcoholism and Anxiety Disorders
Clinical studies reveal that 23 to 70 percent of patients in alcoholism treatment also suffer from anxiety 3 Tachycardia means "increased heart rate." 4 Dyspnea means "shortness of breath or diffi culty in breathing." disorders, particularly anxiety neuro sis and phobias (Kushner et al. 1990;Merikangas and Angst 1995).Con versely, 20 to 45 percent of patients with anxiety disorders have histories of alcoholism (Kushner et al. 1990).
Much of the variability in the comor bidity rates of anxiety disorders and alcoholism can be attributed to differ ences in the definitions of anxiety em ployed in the studies, the period for which the prevalence was determined, and the groups of alcoholics studied.For example, more people have expe rienced comorbid anxiety and alcohol ism at some time in their lives than at the time they are actually studied (Merikangas et al. 1996a).Moreover, comorbid anxiety disorders occur more commonly among people diag nosed with alcohol dependence than among those diagnosed with alcohol abuse (Helzer and Pryzbeck 1988;Regier et al. 1990b;Kessler et al. 1996).1972).Moreover, many patients with anxiety have used alcohol deliberately to cope in fearinducing situations (Smail et al. 1984;Stockwell et al. 1984).In na tionwide surveys, high school students also have reported reduction in anxiety or tension as a major reason for ado lescent drug use (Johnston et al. 1986).Finally, in many people, anxiety symp toms precede the onset of alcoholism, often by several years, suggesting that alcoholism is secondary to anxiety dis orders (Stockwell et al. 1984;Weiss and Rosenberg 1985;Merikangas et al. 1994).Anxiety may play a role in initiating as well as in maintaining alcoholism (Stockwell et al. 1984).

Mechanisms for Comorbidity
Conversely, alcoholism also may contribute to the development of anxi ety symptoms.For example, anxiety is a common symptom of alcohol with drawal (Schuckit and Monteiro 1988).In addition, prolonged alcohol con sumption leads to a marked deteriora tion of the expression of emotions and feelings (i.e., affect) that is characterized by anxiety and depression (Mendelson and Mello 1966;Nathan et al. 1971).In some people, alcohol also may in duce cardiovascular symptoms (e.g., palpitations, increased heart rate, or sweating) that mimic anxiety or heighten awareness of physical symp toms (Mello and Mendelson 1979).
The role of alcoholism in inducing anxiety was supported by findings that phobias and panic attacks did not persist in alcoholic men who were assessed during hospitalization and after 1 year of followup (Penick et al. 1988).Thus, the timing of assessment appears to be critical when determining the comor bidity of alcoholism and anxiety dis orders.The reliable assessment of cooccurring alcoholism and specific anxiety disorders also is hampered by the fact that in clinical studies, which mostly include male subjects, the num bers of alcoholics with anxiety disorders are small compared with the numbers of alcoholics with other comorbid psy chiatric disorders, such as antisocial personality or other drug abuse.

THE ROLE OF FAMILY STUDIES IN ANALYZING COMORBIDITY OF ALCOHOLISM AND ANXIETY DISORDERS
Family studies compare the prevalence rates of certain disorders among the relatives of subjects (i.e., probands) with the disorders to the relatives of probands without the disorders.Family studies may help discriminate between alternative mechanisms for the co occurrence of two or more disorders by examining the transmission of pure (e.g., alcoholism only) and combined (e.g., al coholism plus anxiety) forms of the dis orders among the relatives of probands with pure and comorbid disorders (Merikangas and Gelernter 1990).For example, family studies have been em ployed to investigate the mechanisms underlying the comorbidity of alcohol ism, anxiety, and depression (Merikan gas et al. 1994).
If two disorders have a causal rela tionship, the relatives of probands with the causal disorder will manifest an increased risk for the pure form of the causal disorder and for the combina tion of both disorders, but not for the pure form of the comorbid disorder.For example, if anxiety caused alco relatives of probands with anxiety should have an increased rate of pure anxiety or anxiety combined with alcoholism, but should have nor mal rates of pure alcoholism.
If the two disorders share a com mon etiology (i.e., similar underlying biochemical defects or detrimental en vironmental factors lead to the devel opment of either disorder), then the relatives of probands with the pure form of one disorder also will exhibit elevated rates of the pure form of the comorbid disorder compared with those of the general population.Con sequently, if alcoholism and anxiety shared a common etiology, the rela tives of probands with pure anxiety also should be at increased risk for pure alcoholism and vice versa.
To discriminate between these alter natives, family studies must include sufficient numbers of probands with pure forms of each disorder as well as of control probands with neither disor der.Using appropriate sampling and diagnostic procedures, one then can estimate differences in the rates of the disorders among the relatives of af fected probands and the relatives of the control probands.When analyzing these data, however, it is important to exclude factors that may lead to over estimates of comorbidity.These factors include, for example, the following: the exclusive use of clinical samples, which may overestimate comorbidity because patients with two disorders are more likely to seek treatment; overlaps in the diagnostic criteria of the disorders studied; and confound ing factors, such as genderspecific differences in the comorbidity of cer tain disorders.

Findings of Previous Family Studies of Alcoholism and Anxiety
Numerous studies have demonstrated that both alcoholism (Merikangas and Gelernter 1990; McGue 1994) and anxiety disorders (Cohen et al. 1951;Noyes et al. 1978;Crowe et al. 1983;Fyer et al. 1993) run in families.Family studies of both alcoholism and anxiety disorders also have reported elevated rates of the other condition among the probands' relatives.For example, first degree relatives of probands with anxi ety disorders exhibited a significantly increased risk for alcoholism (Cohen et al. 1951;Noyes et al. 1978;Munjack and Moss 1981;Harris et al. 1983;Leckman et al. 1983;Maier et al. 1993a).Likewise, anxiety rates were elevated among the relatives of alco holic probands (Merikangas et al. 1985;Maier and Merikangas 1996).These studies, however, generally did not relate the rates of the comorbid disor ders among the relatives to the pres ence or absence of comorbidity in the probands and therefore could not de termine whether the disorders were inherited independently of each other.
Only a few family studies have examined specifically the patterns of cotransmission of alcoholism and anxiety disorders among firstdegree relatives of affected probands (Maier et al. 1993a;Maier and Merikangas 1996).Maier and Merikangas (1996) investigated the comorbidity between affective disorders (e.g., depression), anxiety disorders, and alcoholism, in cluding the patterns of cotransmission of alcoholism and panic disorder.The study's findings suggested that shared susceptibility factors exist for alcohol ism and panic disorder, because the relatives of probands with pure panic disorder also exhibited an elevated risk of alcoholism.Similarly, a recent un controlled family study of anxiety disorders suggested an etiologic rela tionship between anxiety disorders and alcohol and other drug abuse (Skre et al. 1994).
Another study that simultaneously examined the comorbidity and cotrans mission of alcoholism, anxiety, and de pression has yielded evidence that both alcoholism and anxiety can be trans mitted independently within families and that comorbid alcoholism and anxi ety can be cotransmitted (Merikangas et al. 1994).The study did not allow conclusions about the mechanisms underlying cotransmission, however, because it did not include any probands who exhibited pure alcoholism or pure anxiety, and all the alcoholic subjects suffered from secondary alcoholism (i.e., alcoholism caused by depression).Accordingly, another study-the Yale Family Study-was conducted that included probands with pure alcohol ism, pure anxiety disorders, or both disorders and which was designed specifically to investigate the patterns of familial transmission of the co morbidity of alcoholism and anxiety disorders (Merikangas et al. 1996b).Findings from this study are presented in the following sections.

Sample Characteristics
The Yale Family Study included 226 probands, including patients with al coholism and/or anxiety disorders and normal control subjects.The patients were recruited from outpatient specialty clinics at the Connecticut Mental Health Center in New Haven, Connecticut.All patients treated at the clinics over a 3year period were screened for eligibil ity in the study, and those who met the appropriate diagnostic criteria were in vited to participate.The control subjects were randomly selected from the pop ulation of the greater New Haven area.All probands were assigned to one of four lifetime diagnostic groups based on their predominant psychopathology as follows: • Fortytwo probands met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) for alcohol dependence.
• Seventysix probands met the DSM-III-R criteria for an anxiety disorder.
• Fortyseven probands fulfilled the DSM-III-R criteria for both alcohol dependence and an anxiety disorder.
• Sixtyone normal control subjects had no history of a DSM-III-R axis I disorder (i.e., a major psy chiatric disorder, such as an affec tive disorder, an anxiety disorder, substance abuse or dependence, or antisocial personality).
The presence or absence of alco holism and anxiety disorders in the probands' firstdegree relatives and spouses was assessed through semi structured diagnostic interviews.Family history information on all families also was obtained using semistructured diagnostic interviews.

Prevalence of Alcoholism and Anxiety in Relatives
The relatives of probands who were alcohol dependent and/or had an anxiety disorder were at an increased risk for developing alcohol dependence and/or an anxiety disorder themselves (table 1).For example, whereas 4 percent of the relatives of the control probands developed alcohol dependence, the rate among relatives of alcoholdependent probands was 15 percent.Similarly, the rate of anxiety disorders was 13 percent among relatives of control probands but 21 percent among relatives of probands with anxiety disorders.The rates of al cohol dependence and anxiety disorders also were increased in the relatives of probands with comorbid alcohol depen dence and anxiety disorders.Finally, the presence of anxiety disorders in the probands slightly increased the risk for alcohol dependence in their relatives, whereas alcohol dependence in the probands did not increase their relatives' risk for anxiety disorders.
Similarly, Maier and colleagues (1993b) demonstrated an increased risk of alcoholism in probands with panic disorder, but not the reverse.These findings suggest some role for shared etiologic factors in the co morbidity of alcoholism and anxiety disorders that could account for the increased risk of alcoholism in rela tives of probands with anxiety disor ders.These shared etiologic factors could include genetic factors predis posing to both types of disorders, bio logical environmental risk factors, nonbiological environmental factors (e.g., a disruptive family environment or parental abuse or neglect), or expo sure to prenatal environmental factors (e.g., maternal alcohol use).The mani festation of a particular disorder could then be determined by the timing of the exposure to the risk factors and/or the influence of additional genetic or envi ronmental factors.Findings from a study mon genetic factors may underlie both alcoholism and panic disorder at least to some extent (Kendler et al. 1995).
To analyze further the comorbid ity of alcoholism and anxiety disorders in the relatives of all probands, cal culations (i.e., odds ratios) of alcohol dependent male and female relatives were computed for developing specific anxiety disorders as well as other psy chiatric disorders (table 2).These odds ratios indicate whether alcohol depen dence and other disorders are associated by comparing the proportion of rela tives concordant for the two disorders (i.e., who have either both disorders or none of them) to the proportion of rel atives discordant for the two disorders (i.e., who experience either alcohol de pendence without anxiety or anxiety without alcohol dependence).
The analyses demonstrated that alcoholdependent male relatives were about twice as likely to exhibit an anxi ety disorder as nonalcoholdependent male relatives, whereas for female alcoholdependent relatives, the likeli hood was increased 3.7 times.These findings indicate that in addition to a person's family history, other factors, such as gender, influence the risk for comorbid disorders.For certain anxiety disorders, the gender differences were even more significant.For example, the odds ratio for comorbid panic disorder was 0.6 for alcoholdependent male relatives but 4.2 for alcoholdependent female relatives.Similar genderspecific of female twins indicate that com The adjusted odds ratios are calculated by comparing the proportion of relatives who are concordant for the two disorders (i.e., have both alcoholism and another disorder or have none of these disorders) with the proportion of relatives who are discordant for the two disorders (i.e., have either alcoholism and no other disorder or vice versa).
2 These diagnoses are not mutually exclusive.
differences existed for some comorbid affective disorders, such as major de pression and bipolar disorder.

Comorbidity and Cotransmission of Alcohol Dependence Versus Alcohol Abuse
Using complex statistical analyses that took into consideration the probands' disorders, the relatives' disorders, and other factors including the relatives' ages, gender, and interview status (e.g., direct interview versus family history information), the Yale Family Study also compared the risk ratios5 for the development of alcohol abuse and al cohol dependence in the relatives.The results reveal that alcohol dependence in the probands was more strongly as sociated with alcohol dependence than with alcohol abuse in the relatives (table 3).For example, 24 percent of the relatives of alcoholdependent pro bands met the lifetime criteria for alco hol dependence compared with only 7 percent of the relatives of the control subjects, yielding a risk ratio of approx imately 3.In contrast, the differences in alcohol abuse rates among the relatives of the alcoholdependent probands (10 percent) and the relatives of the control subjects (7 percent) were not significant.
In general, the risk of alcoholism was higher in male relatives than in female relatives and lower in older relatives than in younger ones (i.e., in earlier birth cohorts).These observations confirm the results of a previous study demonstrating significantly greater heritability of alcohol dependence than of alcohol abuse (Pickens et al. 1991).Furthermore, they validate the distinc tion between alcohol abuse and de pendence introduced by Edwards and Gross (1976) and implemented in the DSM-III-R and other subsequent diag nostic schemes.Anxiety disorders in the probands also were significantly associated with alcohol dependence (adjusted risk ratio of 1.46) but not alcohol abuse (adjusted risk ratio of 0.99) in the relatives (table 3).Thus, anxiety disorders in the pro bands conveyed an increased risk of alcohol dependence in their relatives even after controlling for the familial transmission of alcoholism and other risk factors, including sex, age, and interview status of the relatives.These findings support the hypothesis men tioned previously that alcohol depen dence and anxiety disorders may result, at least in part, from shared underlying risk factors.Analyses of a sample of female twins revealed that the shared liability for anxiety disorders and al coholism is partially attributable to common genetic risk factors (Kendler et al. 1995).

Associations Between Alcoholism and Anxiety
The results of the Yale Family Study confirmed the wellestablished famil ial aggregation of both anxiety disor ders and alcoholism as well as the common comorbidity between both types of disorders.The frequency of the observed comorbidity of alcohol ism and other major psychiatric disor ders also was consistent with the results of previous clinical and epidemiologi cal studies in which alcoholism was strongly associated with antisocial personality disorder, affective disorders, and anxiety disorders.These findings illustrate the importance of using family The Yale Family Study also found evidence of gender differences in the comorbidity between alcoholism and specific anxiety disorders.Previous studies had found higher general psy chiatric comorbidity in women (Angst et al. 1990) but had not systematically addressed gender differences in the comorbidity of alcoholism and anxiety.Moreover, these studies frequently had yielded inconsistent results regarding genderspecific comorbidity (Smail et al. 1984;Chambless et al. 1987), in part because many clinical studies were limited to male alcoholics or included only small sample sizes, resulting in nonrepresentative comorbidity rates.

Implications for Diagnosis, Treatment, and Prevention
The findings regarding the comorbidi ty and cotransmission of alcoholism and anxiety disorders have important implications for the diagnostic classi fication, treatment, and prevention of these disorders.For example, both the Yale Family Study and the investiga tion by Pickens and colleagues (1991) underscored the significance of the distinction between alcohol abuse and alcohol dependence used in current diagnostic classification systems.Both studies demonstrated that alcohol de pendence was strongly transmissible in families, whereas alcohol abuse was not.Accordingly, investigators should pay attention to the diagnostic status of their subjects, and research or clini cal studies that include both probands with alcohol abuse and with alcohol dependence may not be able to detect certain relationships between alco holism and other related factors or disorders.For example, studies of the associations between alcoholism and biological markers should focus on subjects who are alcohol dependent, whereas studies of the role of envi ronmental factors in alcoholism de velopment could perhaps best be addressed using subjects diagnosed with alcohol abuse.
The comorbidity of alcoholism and anxiety disorders also may affect the evaluation and treatment of individuals with these conditions, irrespective of the disorder for which these people seek treatment.For example, alco holics with comorbid anxiety experi ence more severe alcohol withdrawal and an increased tendency to relapse (Johnston et al. 1991;LaBounty et al. 1992).Conversely, alcoholism result ing from selfmedication with alcohol often goes unrecognized in treatment settings for anxiety disorders.In fact, alcohol withdrawal can closely mimic the symptoms of panic and general ized anxiety.Furthermore, persons with comorbid anxiety and alcoholism often manifest additional comorbid disorders, particularly affective disor ders.Consequently, when designing longterm treatment strategies, one must evaluate potential manifestations of anxiety and depression during alco hol withdrawal and subsequent absti nence (Anthenelli and Schuckit 1993).
The relationships between alcohol ism and anxiety disorders described in this article also provide key informa tion for both primary and secondary prevention of these disorders.For ex ample, family histories of these condi tions can serve as important indicators of an increased risk for the disorders in the offspring of these families.More over, the existence of a potential etio logical pathway from anxiety disorders to alcoholism suggests that children experiencing high levels of anxiety symptoms or anxiety disorders have a heightened risk for using alcohol to self medicate anxiety symptoms, particularly in the presence of other known risk factors for alcoholism.The early identi fication and treatment of these children could help prevent potential subsequent alcohol abuse and dependence.■

Table 1
Comorbidity of Alcohol Dependence and Anxiety in Subjects (i.e., Probands) and Their Relatives Participating in the Yale Family Study

Table 2
Adjusted Odds Ratios 1 of the Comorbidity of Psychiatric Disorders in AlcoholDependent Male and Female Relatives of Subjects (i.e., Probands) in the Yale Family Study

Table 3
Adjusted Risk Ratios 1 for the Comorbidity and Cotransmission of Alcohol Dependence or Alcohol Abuse and Anxiety Disorders Among Subjects (i.e., Probands) and Their Relatives in the Yale Family Study

Adjusted Risk Ratio of Alcohol Dependence or Abuse in Relatives of Probands
Similar to odds ratios, risk ratios provide a measure of the association between two disorders by comparing the risks for alcohol dependence or alcohol abuse in relatives of probands with alcohol dependence or anxiety to the risks for relatives of probands without alcohol dependence or anxiety.